Radomsky Lena M-L, Kühne Jenny F, Beushausen Kerstin, Keil Jana, Knigina Ludmilla, Scheibner Yves, Görler Adelheid, Ruhparwar Arjang, Ius Fabio, Bara Christoph L, Falk Christine S
Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany.
Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Front Cardiovasc Med. 2025 Aug 8;12:1612258. doi: 10.3389/fcvm.2025.1612258. eCollection 2025.
Rejection remains a limiting factor for survival after heart transplantation (HTx), and predictive biomarkers are still missing. Therefore, we aimed to define the cytokine/chemokine microenvironment in endomyocardial biopsies (EMB) and plasma after HTx and to identify patterns that reflect ischemia/reperfusion injury as well as allograft rejection. Therefore, we hypothesize distinct cytokine/chemokine patterns in heart biopsies with histopathologically proven rejection compared with the microenvironment in unsuspicious biopsies.
EMB ( = 181; = 52 patients) and peripheral blood samples ( = 147; = 52 patients) were obtained between 6 days and 5 years after HTx. 50 immune proteins in EMB tissue lysates and plasma were quantified, and concentrations were compared between EMB with and without histopathologically defined acute rejection (AR), and correlation analyses between tissue and plasma were performed.
Regarding rejection status, distinct cytokine/chemokine patterns were identified with significantly higher concentrations of CCL4, CXCL9, and CXCL10 in EMB with acute rejection ( < 0.001). In addition, we identified individual long-term dynamics of patients after HTx associated with rejection. Elevated chemokine concentrations were also detected in EMB of patients with donor-specific antibodies (DSAs). Moreover, significantly different patterns were observed between heart tissue and plasma without direct correlations.
A core signature was defined for EMB with histopathologically proven AR, consisting of high concentrations of CXCL9, CXCL10, CCL3, and CCL4. This EMB chemokine signature was clearly distinct from plasma samples, arguing for a local protein microenvironment associated with AR. Further research is also needed with the help of AI to translate the different approaches for the detection and prediction of AR into clinical practice.
排斥反应仍然是心脏移植（HTx）后影响生存的一个限制因素，且目前仍缺乏预测性生物标志物。因此，我们旨在确定HTx后心内膜心肌活检（EMB）和血浆中的细胞因子/趋化因子微环境，并识别反映缺血/再灌注损伤以及同种异体移植排斥反应的模式。因此，我们推测与无可疑活检的微环境相比，经组织病理学证实有排斥反应的心脏活检中存在不同的细胞因子/趋化因子模式。
在HTx后6天至5年期间获取EMB（n = 181；来自52例患者）和外周血样本（n = 147；来自52例患者）。对EMB组织裂解物和血浆中的50种免疫蛋白进行定量，并比较有和无组织病理学定义的急性排斥反应（AR）的EMB之间的浓度，并进行组织与血浆之间的相关性分析。
关于排斥反应状态，在急性排斥反应的EMB中鉴定出不同的细胞因子/趋化因子模式，其中CCL4、CXCL9和CXCL10的浓度显著更高（P < 0.001）。此外，我们确定了HTx后患者与排斥反应相关的个体长期动态变化。在有供体特异性抗体（DSA）的患者的EMB中也检测到趋化因子浓度升高。此外，在心脏组织和血浆之间观察到明显不同的模式，且无直接相关性。
为经组织病理学证实有AR的EMB定义了一个核心特征，包括高浓度的CXCL9、CXCL10、CCL3和CCL4。这种EMB趋化因子特征与血浆样本明显不同，表明存在与AR相关的局部蛋白质微环境。还需要借助人工智能进行进一步研究，以将检测和预测AR的不同方法转化为临床实践。
